A mechanistic study on the enhanced antihypertensive effects of a Dendrobium officinale compound combined with Western antihypertensive drugs in spontaneously hypertensive rats based on metabolomics and gut microbiota analysis

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Background: In our previously published research, we reported that the combination of Dendrobium Officinale Compound (DOC) and antihypertensive medications (irbesartan and amlodipine besylate) significantly and stably regulates blood pressure in spontaneously hypertensive rats (SHRs). This study aims to further explore the unique mechanisms and pathway networks underlying the antihypertensive effects of this combination therapy at the molecular level, based on serum and ileocecal contents metabolomics as well as gut microbiota analysis. Methods: Utilizing UPLC-Q-TOF/MS and metabolomics techniques, we collected, analyzed, and integrated metabolite data to identify differential small molecule metabolites. High-throughput sequencing of the 16S rRNA gene was employed to characterize differences in gut microbiota composition among experimental animals subjected to distinct pharmacological interventions, and further elucidating the underlying antihypertensive mechanism network associated with the combined administration of DOC and conventional antihypertensive drugs. Results: Metabolomic analyses revealed substantial differences in the profiles of low-molecular-weight metabolites in both serum and ileocecal contents across all treatment groups compared with the model control group. The antihypertensive effects of medium- and high-dose DOC in SHRs were associated with differential metabolites including L-tyrosine, L-methionine, and L-arginine; in contrast, the enhanced antihypertensive effect observed upon combination therapy with DOC and Western antihypertensive drugs correlated with distinct metabolites such as pregnenolone, creatine, and L-phenylalanine. 16S rRNA gene high-throughput sequencing of ileocecal contents indicated that the relative abundance of Firmicutes increased by 8.73%, 0.84%, and 10.40% following low-, medium-, and high-dose DOC interventions, respectively, relative to the model group; however, combination therapy with DOC and Western antihypertensive drugs resulted in an 8.80% decrease in Firmicutes abundance compared with the model group. Conversely, the relative abundance of Bacteroidetes decreased by 7.60%, 3.31%, and 7.67% after low-, medium-, and high-dose DOC treatments, respectively, versus the model group; yet, combination therapy led to a 7.05% increase in Bacteroidetes abundance relative to the model group. Conclusion: Metabolomic and 16S rRNA sequencing analyses revealed that these effects may be linked to DOC's specific modulation of serum amino acid profiles and remodeling of gut microbiota composition in PCAs. These findings provide new mechanistic insights into this traditional herb's antihypertensive action.

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